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Metabotropic Glutamate Receptors in the Control of Mood Disorders

机译：控制情绪障碍的代谢型谷氨酸受体

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Current treatments for depression are less than optimal in terms of onset of action, response and remission rates, and side-effect profiles. Glutamate is the major excitatory neurotransmitter controlling synaptic excitability and plasticity in most brain circuits, including limbic pathways involved in depression. Thus, drugs that target glutamate neuronal transmission offer novel approaches to treat depression. Recently, the NMDA receptor antagonist ketamine has demonstrated clinical efficacy in a randomized clinical trial of depressed patients. Metabotropic glutamate (mGlu) receptors function to regulate glutamate neuronal transmission by altering the release of neurotransmitter or modulating the post-synaptic responses to glutamate. Accumulating evidence from biochemical and behavioral studies support the idea that the regulation of glutamatergic neurotransmission via mGlu receptors is linked to mood disorders and that these receptors may serve as novel targets for the discovery of small molecule modulators with unique antidepressant properties. For example, mGlu receptor modulation can facilitate neuronal stem cell proliferation (neurogenesis) and the release of neurotransmitters that are associated with treatment response to depression in humans (serotonin, norepinephrine, dopamine). In particular, compounds that antagonize mGlu2, mGlu3 and/or mGlu5 receptors (e.g. LY341495, MSG0039, MPEP) have been linked to the above pharmacology and have also shown in vivo activity in animal models predictive of antidepressant efficacy such as the forced-swim test. The in vivo actions of these agents can be antagonized by compounds that block AMPA receptors, suggesting that their actions are direct downstream consequences of the enhancement of glutamate neuronal transmission in brain regions involved in depression. These data provide new approaches to finding mechanistically distinct drugs for depression that may have advantages over current therapies for some patients. Moreover, since the mood disorders encompase a non-homogenous set of symptoms, comorbid disorders, and potential etiologies, the rich arsensel that exists within the mGlu receptor families provides an opportunity for both broad and customized therapeutics.
机译：就作用的发作，反应和缓解率以及副作用情况而言，目前对抑郁症的治疗均未达到最佳效果。谷氨酸是主要的兴奋性神经递质，可控制大多数大脑回路（包括与抑郁有关的边缘途径）的突触兴奋性和可塑性。因此，靶向谷氨酸神经元传递的药物提供了治疗抑郁症的新方法。最近，NMDA受体拮抗剂氯胺酮已在抑郁症患者的随机临床试验中证明了临床疗效。代谢型谷氨酸（mGlu）受体的功能是通过改变神经递质的释放或调节对谷氨酸的突触后反应来调节谷氨酸的神经元传递。来自生化和行为研究的越来越多的证据支持这样的想法，即通过mGlu受体调节谷氨酸能神经传递与情绪障碍有关，并且这些受体可以作为发现具有独特抗抑郁特性的小分子调节剂的新靶标。例如，mGlu受体调节可以促进神经元干细胞的增殖（神经发生）和神经递质的释放，这些递质与人类对抑郁症的治疗反应有关（5-羟色胺，去甲肾上腺素，多巴胺）。尤其是，拮抗mGlu2，mGlu3和/或mGlu5受体的化合物（例如LY341495，MSG0039，MPEP）已与上述药理联系起来，并且在动物模型中也显示出体内活性，可预测抗抑郁功效，例如强迫游泳试验。阻断AMPA受体的化合物可拮抗这些药物的体内作用，这表明它们的作用是参与抑郁症的大脑区域中谷氨酸神经元传递增强的直接下游后果。这些数据提供了寻找机制不同的抑郁症药物的新方法，对于某些患者而言，这些药物可能比目前的治疗方法具有优势。此外，由于情绪障碍包括一组不均一的症状，合并症和潜在病因，因此存在于mGlu受体家族中的丰富砷为广泛和定制的治疗方法提供了机会。

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